T lymphocytes must respond to specific antigen by rapid proliferation and differentiation to mount an effective immune response. It is critical that this occur only in response to foreign antigen, so that self antigens do not induce autoimmune responses. T cell tolerance to self antigen is achieved by negative selection in the thymus to eliminate clones that recognize self antigen. In addition, mechanisms exist for rendering mature T cells in the periphery tolerant to antigens. This Program is addressing the nature of these mechanisms in thymocytes and mature T cells at the molecular and cellular levels using both in vitro and in vivo models. Peripheral tolerance in CD4 plus T cells is being studied in the first Project and second Project, negative selection of class I restricted thymocytes is being examined in the third Project and peripheral tolerance of CD8 plus T cells is being examined in the fourth Project. Thus, the four projects of the Program examine two major types of T cells, CD4 plus cells and CD8 plus cells. The planned work involves extensive collaborative interactions among the investigators of each project. It is anticipated that the findings obtained in the planned studies will contribute to a better fundamental understanding of how autoimmunity is avoided. In addition, understand of these mechanisms, and hence the ability to manipulate them, has the potential to contribute to improvements in transplantation and disease therapy. Mechanisms that induce tolerance to self antigens may also induce tolerance to foreign antigens including those present on tumors or virus-infected cells, resulting in the immune system failing to mount a protective response. Finally, there is great potential for using defined peptide antigens to induce protective or therapeutic immunity for a broad range of disease and much current effort is focusing on this. However, it is becoming increasingly clear that these must be used with great caution since they can also induce tolerance which may lead to lessened protection or excaccerbated disease. Thus, developing a better understanding of the mechanisms that can lead to T cell tolerance, as proposed in this Program, has implications well beyond autoimmune diseases.